In vitro and in vivo evidence for a role of the P2X7 receptor in the release of IL-1β in the murine brain

• Published in: Brain, behavior, and immunity Vol. 22; no. 2; pp. 234 - 244
• Main Authors: Mingam, Rozenn, Smedt, Véronique De, Amédée, Thierry, Bluthé, Rose-Marie, Kelley, Keith W, Dantzer, Robert, Layé, Sophie
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier 01.02.2008
• Subjects: Allergy and Immunology; Animals; Astrocytes - cytology; Astrocytes - drug effects; Astrocytes - immunology; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters - metabolism; Cells, Cultured; Coculture Techniques; Hypothalamus - cytology; Hypothalamus - immunology; Hypothalamus - metabolism; Interleukin-1beta - metabolism; Interleukin-6 - metabolism; Life Sciences; Lipopolysaccharides - pharmacology; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia - cytology; Microglia - drug effects; Microglia - immunology; Neuroimmunomodulation - immunology; Psychiatry; Receptors, Purinergic P2 - genetics; Receptors, Purinergic P2 - immunology; Receptors, Purinergic P2 - metabolism; Receptors, Purinergic P2X7; Tumor Necrosis Factor-alpha - metabolism; Brain; TNFα; P2X 7R knockout mice; ABC1 transporter; RT-PCR; Astrocyte; IL-1β; IL-6; LPS; Microglia; ABC1 TRANSPORTER; P2X7R KNOCKOUT MICE; MICROGLIA; ASTROCYTE; LIPOPOLYSACCHARIDE; BRAIN
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2007.08.007

Abstract The P2X7 receptor (P2X7 R) is a purinoceptor expressed predominantly by cells of immune origin, including microglial cells. P2X7 R has a role in the release of biologically active proinflammatory cytokines such as IL-1β, IL-6 and TNFα. Here we demonstrate that when incubated with lipopolysaccharide (LPS), glial cells cultured from brain of P2X7 R−/− mice produce less IL-1β compared to glial cells from brains of wild-type mice. This is not the case for TNFα and IL-6. Our results indicate a selective effect of the P2X7R gene deletion on release of IL-1β release but not of IL-6 and TNFα. In addition, we confirm that only microglial cells produce IL-1β, and this release is dependent on P2X7 R and ABC1 transporter. Because IL-1β is a key regulator of the brain cytokine network and P2X7 R is an absolute requirement for IL-1β release, we further investigated whether response of brain cytokines to LPS in vivo was altered in P2X7 R−/− mice compared to wild-type mice. IL-1β and TNFα mRNAs were less elevated in the brain of P2X7 R−/− than in the brain of wild-type mice in response to systemic LPS. These results show that P2X7R plays a key role in the brain cytokine response to immune stimuli, which certainly applies also to cytokine-dependent alterations in brain functions including sickness behavior.